ABSTRACT. Age-related hearing loss is a common disorder defined as the loss of the hearing with aging. In the United States, approximately 33% of the population between ages of 65 and 74 are subjected to hearing loss, and after 75 years of age, about 50% of the population have hearing problems. There are many causes of age-related hearing loss, including age-induced changes in the in the inner and middle ear and also complex changes along the nerve pathways from the ear to the brain. Epidemiological studies, such as The Epidemiology of Hearing Loss Study and National Health and Nutrition Examination Survey 1999-2004, have shown that the major risk factors for age-related hearing loss are noise exposure and smoking. Very limited information is available regarding the molecular pathways involved in age-related hearing loss and how smoking behaviors increase its risk. Our previous results suggest that genetic variation can play a role in moderating the effect of smoking on age-related hearing loss reducing smoking-induced damage in brain regions involved in auditory function. In the current proposal, we will apply genome-wide approaches to identify additional mechanisms involved in the age-related hearing loss induced by smoking behaviors. Specifically, we will conduct a genome-wide association study of age- related hearing loss in more than 500,000 subjects (>150,000 nicotine-exposed, >350,000 nicotine-unexposed). We will use the genetic and phenotypic information from cohorts from the UK Biobank, the Nurses' Health Studies I and II, the Health Professionals Follow-Up Study, and the National Center for Biotechnology Information the database of Genotypes and Phenotypes to conduct a genome-wide association study of hearing loss in individuals exposed to nicotine. A follow-up study will be performed with respect brain structure and activity using magnetic resonance imaging data from the UK Biobank. Additionally, we will conduct a multivariable Mendelian Randomization to investigate which metabolomic alterations and/or brain-structure changes mediate the causal relationship between smoking and hearing loss. The goal of this analysis is to verify the causal effect and the mediation processes involved in the interplay between smoking behaviors and hearing loss. The expected findings will provide novel insights regarding the molecular mechanisms by which smoking behaviors cause age-related hearing loss A better understanding of its genetics could permit us to develop more effective preventive strategies and therapeutic approaches that can improve the quality of life of the growing elderly population.